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Localization of MMR proteins on meiotic chromosomes in mice indicates distinct functions during prophase I.

Kolas NK, Svetlanov A, Lenzi ML, Macaluso FP, Lipkin SM, Liskay RM, Greally J, Edelmann W, Cohen PE - J. Cell Biol. (2005)

Bottom Line: Mutations of three of the four MutL homologues (Mlh1, Mlh3, and Pms2) result in meiotic defects.This complex is up-regulated in Pms2-/- males, but not females, providing an explanation for the sexual dimorphism seen in Pms2-/- mice.The association of MLH3 with repetitive DNA sequences is coincident with MSH2-MSH3 and is decreased in Msh2-/- and Msh3-/- mice, suggesting a novel role for the MMR family in the maintenance of repeat unit integrity during mammalian meiosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

ABSTRACT
Mammalian MutL homologues function in DNA mismatch repair (MMR) after replication errors and in meiotic recombination. Both functions are initiated by a heterodimer of MutS homologues specific to either MMR (MSH2-MSH3 or MSH2-MSH6) or crossing over (MSH4-MSH5). Mutations of three of the four MutL homologues (Mlh1, Mlh3, and Pms2) result in meiotic defects. We show herein that two distinct complexes involving MLH3 are formed during murine meiosis. The first is a stable association between MLH3 and MLH1 and is involved in promoting crossing over in conjunction with MSH4-MSH5. The second complex involves MLH3 together with MSH2-MSH3 and localizes to repetitive sequences at centromeres and the Y chromosome. This complex is up-regulated in Pms2-/- males, but not females, providing an explanation for the sexual dimorphism seen in Pms2-/- mice. The association of MLH3 with repetitive DNA sequences is coincident with MSH2-MSH3 and is decreased in Msh2-/- and Msh3-/- mice, suggesting a novel role for the MMR family in the maintenance of repeat unit integrity during mammalian meiosis.

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Localization of MLH1 and MLH3 to Y chromosome centromere region. Immunogold-EM localization of MLH1 (6 nm gold grains, green arrows), MLH3 (12 nm gold grains, red arrows), and CREST (18 nm gold grains, blue arrows) on meiotic chromosome cores of Pms2−/− sex chromosomes. The p-arm of the Y chromosome is cytologically distinct from the q-arm, which contains the PAR that synapses with the PAR of the X chromosome. Due to the length of the p-arm, the Y chromosome centromere (top inset) can be differentiated from the terminally located telomere and both MLH1 and MLH3 localize to both the X (bottom inset) and the Y chromosome centromere. SCs are counterstained with phosphotungstic acid. Bar, 500 nm.
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fig3: Localization of MLH1 and MLH3 to Y chromosome centromere region. Immunogold-EM localization of MLH1 (6 nm gold grains, green arrows), MLH3 (12 nm gold grains, red arrows), and CREST (18 nm gold grains, blue arrows) on meiotic chromosome cores of Pms2−/− sex chromosomes. The p-arm of the Y chromosome is cytologically distinct from the q-arm, which contains the PAR that synapses with the PAR of the X chromosome. Due to the length of the p-arm, the Y chromosome centromere (top inset) can be differentiated from the terminally located telomere and both MLH1 and MLH3 localize to both the X (bottom inset) and the Y chromosome centromere. SCs are counterstained with phosphotungstic acid. Bar, 500 nm.

Mentions: Considering mouse centromeres are telocentric, we examined whether the accumulation of MLH1–MLH3 at the centromere region in Pms2−/− spermatocytes was due to the centromere per se or the closely-adjacent telomere. We did not observe elevated MLH1–MLH3 accumulation at the distal telomere of Pms2−/− males (Fig. 2 F). Moreover, the Y chromosome, which has a larger expanse between the proximal telomere and the centromere, showed specific accumulation to the centromeric region (Fig. 3), leading us to conclude that the accumulation of MLH3 at these regions was associated specifically with centromere-associated sequences. The presence of MLH3 at centromere regions in wild-type and Mlh1−/− spermatocytes indicates that MLH3 is able to localize to the chromosome independently of MLH1, as it does at early MNs (Fig. 1, B and C).


Localization of MMR proteins on meiotic chromosomes in mice indicates distinct functions during prophase I.

Kolas NK, Svetlanov A, Lenzi ML, Macaluso FP, Lipkin SM, Liskay RM, Greally J, Edelmann W, Cohen PE - J. Cell Biol. (2005)

Localization of MLH1 and MLH3 to Y chromosome centromere region. Immunogold-EM localization of MLH1 (6 nm gold grains, green arrows), MLH3 (12 nm gold grains, red arrows), and CREST (18 nm gold grains, blue arrows) on meiotic chromosome cores of Pms2−/− sex chromosomes. The p-arm of the Y chromosome is cytologically distinct from the q-arm, which contains the PAR that synapses with the PAR of the X chromosome. Due to the length of the p-arm, the Y chromosome centromere (top inset) can be differentiated from the terminally located telomere and both MLH1 and MLH3 localize to both the X (bottom inset) and the Y chromosome centromere. SCs are counterstained with phosphotungstic acid. Bar, 500 nm.
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Related In: Results  -  Collection

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fig3: Localization of MLH1 and MLH3 to Y chromosome centromere region. Immunogold-EM localization of MLH1 (6 nm gold grains, green arrows), MLH3 (12 nm gold grains, red arrows), and CREST (18 nm gold grains, blue arrows) on meiotic chromosome cores of Pms2−/− sex chromosomes. The p-arm of the Y chromosome is cytologically distinct from the q-arm, which contains the PAR that synapses with the PAR of the X chromosome. Due to the length of the p-arm, the Y chromosome centromere (top inset) can be differentiated from the terminally located telomere and both MLH1 and MLH3 localize to both the X (bottom inset) and the Y chromosome centromere. SCs are counterstained with phosphotungstic acid. Bar, 500 nm.
Mentions: Considering mouse centromeres are telocentric, we examined whether the accumulation of MLH1–MLH3 at the centromere region in Pms2−/− spermatocytes was due to the centromere per se or the closely-adjacent telomere. We did not observe elevated MLH1–MLH3 accumulation at the distal telomere of Pms2−/− males (Fig. 2 F). Moreover, the Y chromosome, which has a larger expanse between the proximal telomere and the centromere, showed specific accumulation to the centromeric region (Fig. 3), leading us to conclude that the accumulation of MLH3 at these regions was associated specifically with centromere-associated sequences. The presence of MLH3 at centromere regions in wild-type and Mlh1−/− spermatocytes indicates that MLH3 is able to localize to the chromosome independently of MLH1, as it does at early MNs (Fig. 1, B and C).

Bottom Line: Mutations of three of the four MutL homologues (Mlh1, Mlh3, and Pms2) result in meiotic defects.This complex is up-regulated in Pms2-/- males, but not females, providing an explanation for the sexual dimorphism seen in Pms2-/- mice.The association of MLH3 with repetitive DNA sequences is coincident with MSH2-MSH3 and is decreased in Msh2-/- and Msh3-/- mice, suggesting a novel role for the MMR family in the maintenance of repeat unit integrity during mammalian meiosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

ABSTRACT
Mammalian MutL homologues function in DNA mismatch repair (MMR) after replication errors and in meiotic recombination. Both functions are initiated by a heterodimer of MutS homologues specific to either MMR (MSH2-MSH3 or MSH2-MSH6) or crossing over (MSH4-MSH5). Mutations of three of the four MutL homologues (Mlh1, Mlh3, and Pms2) result in meiotic defects. We show herein that two distinct complexes involving MLH3 are formed during murine meiosis. The first is a stable association between MLH3 and MLH1 and is involved in promoting crossing over in conjunction with MSH4-MSH5. The second complex involves MLH3 together with MSH2-MSH3 and localizes to repetitive sequences at centromeres and the Y chromosome. This complex is up-regulated in Pms2-/- males, but not females, providing an explanation for the sexual dimorphism seen in Pms2-/- mice. The association of MLH3 with repetitive DNA sequences is coincident with MSH2-MSH3 and is decreased in Msh2-/- and Msh3-/- mice, suggesting a novel role for the MMR family in the maintenance of repeat unit integrity during mammalian meiosis.

Show MeSH
Related in: MedlinePlus